Project Summary Social bonds between family members and friends can last a lifetime. As long as these attachments exist, the selective motivation that drives us to seek out and interact with these individuals represents a healthy, reinforcing mechanism that maintains these bonds. But what happens to these motivational systems when a bond is permanently lost? Most people eventually learn to adapt to the loss of a loved one, but for some, the failure to adapt leads to function-impairing grief that can last years. Clinically, this is known as complicated grief. Despite the central importance of socio-motivational processes and their appropriate transformation following loss, their neuronal basis remains unclear. To address this deficit, I propose to use monogamous prairie voles, which form life-long bonds and exhibit distress following separation from their partner. Pair-bonded prairie voles will lever- press to be reunited with their partner, enabling us to quantify bond-directed motivation. My lab is developing a high-throughput operant system to quantify bond-directed motivation. I will combine this novel behavioral paradigm with advanced neurogenetic tools to interrogate the neuronal substrates of bond-directed motivation. I will test whether bond strength predicts levels of partner-directed motivation and how quickly this motivation extinguishes following permanent partner separation. Then, using our operant paradigm in combination with in vivo Ca2+ imaging and cell-specific manipulations of neuronal activity, I will test the hypothesis that distinct neuronal populations within reward-related brain regions modulate partner-directed motivation. Finally, because some people experience pathological forms of grief characterized by persistent dwelling on the lost bond, I will ask whether artificially reactivating the neuronal ensemble that encodes a pair bond leads to prolonged motivational responses following bond loss. Completion of these experiments will provide fundamental insights into the engagement of social motivation systems at a neuronal level ? both when a bond remains intact and following its disruption. There is a pressing need for this research; there are no currently accepted paradigms for studying selective social motivation or the emotional response to loss. As the U.S. population ages, there will be a substantial public-health burden from increased rates of bereavement-induced mental illness, heart disease, and complicated grief, and this work represents a means to elucidate important biological mechanisms that contribute to these phenomena.